cardiovagal baroreflex deficits impair neurovascular coupling and cognition in pots

Conditions: Postural Orthostatic Tachycardia Syndrome (POTS); POTS; Orthostatic Intolerance

Summary: postural tachycardia syndrome (pots), is the chronic form of orthostatic intolerance associated with excessive upright tachycardia, and occurs predominantly in young females (\>85%). among its most troubling symptoms are lightheadedness, fatigue, and decreased memory often called "brain fog" by patients. task-related neurovascular coupling (nvc) links neural activity to an increase in cbf known as "functional hyperemia". although memory task performance and nvc deteriorated with angle of tilt in pots but not healthy controls, cerebral blood flow (cbf) remained similar to control. instead, the investigators observed extensive narrow band low frequency (0.07-0.13 hz) oscillations in bp (obp) that entrained and amplified oscillations in cbf (ocbf). obp and ocbf increased with tilt angle and caused impaired working memory and reduced functional hyperemia. the cardiovagal baroreflex couples bp to hr to buffer bp changes. the investigators hypothesize that the cardiovagal baroreflex becomes progressively impaired with orthostasis in pots, but not in healthy volunteers, and accounts for obp, ocbf, and loss of nvc; further, improving the baroreflex reduces obp, ocbf and brain fog in pots.

orthostatic intolerance is defined by debilitating upright symptoms that are relieved by sitting or lying. symptoms include upright lightheadedness, fatigue, confusion, and decreased memory called 'brain fog' by patients. the most common chronic form is postural tachycardia syndrome (pots), characterized by excessive upright tachycardia without hypotension. of note, \>85% of pots patients are female. the proposal that brain fog was caused by reduced cerebral blood flow (cbf) has been disproven, because graded incremental upright tilt failed to demonstrate difference in mean cbf compared to healthy volunteers. nevertheless, memory task performance deteriorates with angle of tilt as does task-related neurovascular coupling (nvc), which links neural activity to an increase in cbf known as "functional hyperemia". the investigators have previously observed that large low frequency (0.07-0.13 hz) oscillations in bp (obp), which entrained and amplified oscillations in cbf (ocbf), increased with tilt angle and were associated with impaired working memory and reduced functional hyperemia. the sympathetic baroreflex remains intact and hr is excessively increased in the absence of parasympathetic counterregulation. the cardiovagal baroreflex couples bp to hr to buffer bp changes. large low frequency bp oscillations, representing a resonance within the sympathetic baroreflex loop, occur if there is central hypovolemia, an intact sympathetic baroreflex, and reduced parasympathetic buffering of bp by hr; conditions found in upright pots. this leads to the following hypothetical paradigm: ↓cardiovagal baroreflex → ↑obp → ↑↑ocbf → ↓nvc → ↓working memory. therefore, in this application, the investigators hypothesize that the cardiovagal baroreflex is impaired in pots while supine, becomes further impaired with orthostasis, and accounts for obp, ocbf, and loss of nvc. further, the investigators propose that improving the cardiovagal baroreflex improves hemodynamics and brain fog in pots patients.

Eligibility criteria:
inclusion criteria for pots patients: pots patients referred for day to day orthostatic intolerance with greater than 3 symptoms for greater than 3 months and will have the diagnosis of symptomatic postural tachycardia made during a screening tilt table test : * dizziness * nausea and vomiting * palpitations * fatigue * headache * exercise intolerance * blurred vision * abnormal sweating heat. healthy control subjects: * normal physical examination, and normal electrocardiographic and echocardiographic evaluations. * only those free from heart disease, and from systemic illness will be eligible to participate. * this excludes patients with illnesses and disease states known to be associated with endothelial cell dysfunction such as diabetes, renal disease, congestive heart failure, systemic hypertension, acute and chronic inflammatory diseases, neoplasm, immune mediated disease, trauma, morbid obesity and peripheral vascular disease. at the time of testing all patients and control subjects must refrain from vasoactive drugs for two weeks. exclusion criteria for both pots and healthy controls: * an active medical condition that may explain the diagnosis * a previous medical condition with undocumented resolution that may explain the diagnosis * any systemic or overt structural, arrhythmic or myopathic cardiovascular disease * any illnesses known to produce autonomic dysfunction such as diabetes, heart disease, renal disease, systemic hypertension, acute and chronic inflammatory diseases, neoplastic disease, immune mediated disease, major trauma and burns, morbid obesity and peripheral vascular disease will also be excluded. * cigarette smokers will be excluded. * past or present major psychiatric disorder * substance abuse within 2 years before onset of symptoms.

Keywords: postural orthostatic tachycardia syndrome (pots) pots orthostatic intolerance digoxin pyridostigmine mestinon